Project Summary/Abstract Alzheimer's disease (AD) and delirium are common causes of cognitive impairment in older populations that can each lead to functional disability, loss of independence, and higher healthcare costs. While AD and delirium may occur independently, they frequently coexist, resulting synergistically in poorer outcomes. The relationship between AD and delirium is complex, with AD patients at greater risk to develop delirium, and patients with delirium at risk for developing accelerated cognitive decline. Whether delirium is a marker of vulnerability to AD, unmasks unrecognized AD, accelerates preclinical AD, or can itself cause permanent neuronal damage and lead to AD are all poorly understood, and addressing these issues is a high-priority area for aging research. The goals of this R21/R33 phased innovation project is to provide ?proof of concept? for the interrelationship between delirium and AD by exploring potential shared biomarkers between these two conditions. In the R21 phase, we will leverage resources from the NIA-funded Successful Aging after Elective Surgery (SAGES study, P01AG031720), a cohort of 560 persons aged ? 70 years without dementia, 24% of whom developed delirium postoperatively, and who have undergone ? 48 months of periodic detailed cognitive and functional assessments. In a matched parallel case-control study (n=110), candidate biomarkers of neuronal injury, specifically the proteins tau and neurofilament light, and microRNAs (miR), small non-coding RNAs that have been demonstrated to become dysregulated in pathological processes including AD, will be measured in biobanked plasma from SAGES. This will allow for efficient identification of candidate blood-based biomarkers that are predictive of postoperative delirium or long-term cognitive decline (LTCD). In the R33, phase, a new prospective cohort (n=125) of patients scheduled to undergo elective orthopedic surgery under spinal anesthesia will be enrolled to confirm and expand the findings from the R21 phase. As in SAGES, the patients in the R33 cohort will have a comprehensive baseline assessment of medical history, physical and cognitive functioning, and blood sampling, and will be followed prospectively for 12 months from their initial hospitalization with periodic assessments. Cerebrospinal fluid (CSF) will be collected during induction of spinal anesthesia at the time of surgery, and delirium will be assessed daily during hospitalization. Biomarkers from CSF and blood will be used to predict delirium incidence, severity, and cognitive decline. We expect that one or more candidate biomarkers will have utility as a delirium risk, disease, and/or outcome biomarker. Discovery of such biomarkers will contribute to understanding of the interconnection between delirium and dementia; demonstration of a lack of a connection would provide important information as well. Defining the relationship . between neuronal injury and AD-related biomarkers and delirium would advance the pathophysiologic understanding of AD and delirium, and may ultimately aid in the identification of potential targets for effective treatment strategies for both conditions